Note: Descriptions are shown in the official language in which they were submitted.
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A COMPOSITION COMPRISING CAMPTOTHECIN AND A PYRIMIDINE
DERIVATIVE FOR THE TREATMENT OF CANCER
The present invention relates to therapeutic pharmaceutical compositions
comprising an effective amount of a pyrimidine derivative in combination with
an
effective amount of camptothecin or campt~athecin derivatives, which are
useful
for the treatment of cancer.
The invention~relates to the treatment of cancer, especially solid tumors,
with associations of camptothecin derivatives and other anticancer drugs and
the use of such associations for an improved treatment.
More particularly, the present invention provides a synergistic
therapeutic pharmaceutical combination comprising an effective amount of CPT-
11 in combination with an effective amount of capecitabine for the treatment
of a
cancer sensitive to said combination and wherein the effect of the combined
components is synergistic and the use of said composition for the treatment of
a
patient having a cancer.
More specifically, the invention relates to anticancer treatments with
associations of camptothecin derivatives such as irinotecan (CPT-11 ;
Camptosar~), topotecan, 9-aminocamptottiecin and 9-nitrocamptothecin and a
pyrimidine derivative. Pyrimidine derivativta include uracil, thymine,.
cytosine,
methylcytosine and thiamine containing compounds. Examples of such
pyrimidine derivatives are capecitabine, gemcitabine and mufti-targeted
antifolate (MTA), also known as pemetrexed.
European patent EP 137,14;1 describes camptothecin derivatives
of the formula:
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in which, in particular, R, is hydrogen, halogen or alkyl, X is a chlorine
atom or
NR2R3 in which R2 and R3, which may be identical or different, may represent a
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hydrogen atom, an optionally substituted alkyl radical, a carbocycle or a
heterocycle which are optionally substituted, or alkyl radicals (optionally
substituted) forming, with the nitrogen atom to which they are attached, a
heterocycle optionally containing another hetero atom chosen from O, S and/or
s NR4, R4 being a hydrogen atom or an alkyl radical and in which the group
X-CO-O- is located in position 9, 10 or 11 on ring A.
These camptothecin derivatives are anticancer agents which inhibit
topoisomerase I, among which irinotecan, in which X-CO-O- is [4-(1-piperidino-
1-piperidino]carbonyloxy, is an active principle which is particularly
effective in
Io treatment of solid tumors, and in particular, colorectal cancer.
The European patent application EP 74,256 also describes other
camptothecin derivatives which are also mentioned as anticancer agents, in
particular, derivatives of a structure analogous to the structure given above
and
in which X-CO-O- is replaced with a radical -X'R' for which X' is O or S and
R' is
is a hydrogen atom or an alkyl or acyl radical.
Other camptothecin derivatives have also been described, for example, in
the patents or patent applications EP 56,692, EP 88,642, EP 296,612,
EP 321,122, EP 325,247, EP 540,099, EP 737,686, WO 90/03169,
WO 96/37496, WO 96/38146, WO 96/38449, WO 97/00876, US 7,104,894,
2o JP 57 116,015, JP 57 116,074, JP 59 005,188, JP 60 019,790, JP 01 249,777,
JP 01 246,287 and JP 91 12070 or in Canc. Res., 38 (1997) Abst. 1526 or 95
(San Diego -12-16 April), Canc. Res., 55(3):603-609 (1995) or AFMC Int. Med.
Chem. Symp. (1997) Abst. PB-55 (Seoul - 27 July-1 August).
Camptothecin derivatives are usually administered by injection, more
2s particularly intravenously in the form of a sterile solution or an
emulsion.
Camptothecin derivatives, however, can also be administered orally, in the
form
of solid or liquid compositions.
CPT-11 is one of the most active new agents in colorectal cancer.
Colorectal cancer is a leading cause of morbidity and mortality with about
30 300,000 new cases and 200,000 deaths in Europe and the USA each year (See
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P. Boyle, Some Recent Developments in the Epidemiology of Colorectal
Cancer, pages 19-34 in Management of Colorectal Cancer, Bleiberg H.,
Rougier P., Wilke H.J., eds, (Martin Dunitz, London 1998); and - Midgley R.S.,
Kerr D.J., Systemic Adjuvant Chemotherapy for Colorectal Cancer, pages 126-
s 27 in Management of Colorectal Cancer, Bleiberg H., Rougier P., Wilke H.J.,
eds, (Martin Dunitz, London 1998).) Although about fifty percent of patients
are
cured by surgery alone, the other half will eventually die due to metastatic
disease, which includes approximately 25 % of patients who have evidence of
metastases at time of diagnosis.
io In colorectal cancer patients resistant to 5-FU, single agent CPT-11
tested in two large phase III randomized trials resulted in a longer survival
and
a better quality of life compared with supportive care only (D. Cunningham, S.
Pyrhonen, RD. James et al, The Lancet, 352 (9138):1413-1418 (1998)) and also
in a longer survival without deterioration in quality of life compared with 5-
FU/FA
Is best infusional regimens (P. Rougier, E. van Cutsem et al; The Lancet, 352
(9138):1407-1418 (1998)). CPT-11 is therefore the reference treatment in
metastatic colorectal cancer (MCRC) after failure on prior 5-FU treatment.
CPT-11 has also been shown to be at least as active as the so-called
standard 5-FU/FA bolus in chemotherapy naive patients with MCRC [Proc. Am.
2o Soc. Clin. Oncol., vol 13 (1994), (Abstr. # 573) ; J. Clin Oncol, 14(3):709-
715
(1996) ; J. Clin Oncol, 15(1):251-260 (1997).
Combinations of irinotecan (CPT-11 ) and 5-FU have already been
studied in phase I studies in Japan, indicating in preliminary results that
concurrent administration is feasible in terms of safety (L. Saltz et al.,
Eur. J.
Zs Cancer 32A, suppl 3: S24-31 (1996))
A study relating to CPT-11 published by D. Cunningham, Eur. J. Cancer,
32A suppl. 3:S1-8 (1996) concluded that CPT-11 offers a different cytotoxic
approach that may complement the use of 5-FU/folinic acid in colorectal
cancer.
To demonstrate the efficacy of a combination, it may be necessary to
3o compare the maximum tolerated dose of the combination with the maximum
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tolerated dose of each of the separate constituents in the study in question.
This efficacy may be quantified, for example by the logo cells killed, which
is
determined by the following formula:
logo cell killed = T-C(days)/3.32 x Td
s in which T-C represents the time taken for the cells to grow, which is the
mean
time in days for the tumors of the treated group (T) and the tumors of the
treated
group (C) to have reached a predetermined value (1 g for example), and Td
represents the time in days needed for the volume of the tumor in the control
animals (T.H. Corbett et al., Cancer, 40, 2660.2680 (1977); F.M. Schabel et
al.,
io Cancer Drug Development, Part B, Methods in Cancer Research, 17, 3-51, New
York, Academic Press Inc. (1979)). A product is considered to be active if the
logo cell kill is greater than or equal to 0.7. A product is considered to be
very
active is the logo cell kill is greater than 2.8.
The efficacy of a combination may also be demonstrated by
is determination of the therapeutic synergy. A combination manifests
therapeutic
synergy if it is therapeutically superior to one or the other of the
constituents
used at its optimum dose (T.H. Corbett et al., Cancer Treatment Reports, 66,
1187 (1982)).
It has now been found that the combination of camptothecin derivatives
2o with pyrimidine derivatives is especially effective in the treatment of
solid
tumors, such as ovarian, NSCLC and colorectal cancer. Among the effective
pyrimidine derivatives are gemcitabine, MTA, and capecitabine.
Gemcitabine exhibits antitumor activity. The salt of gemcitabine,
2'-deoxy-2',2'-difluorocytidine monohydrochloride, is provided for clinical
use as
?s an intravenous solution for treatment of solid tumors such as non-small
cell lung
cancer (NSCLC).
Gemcitabine exhibits cells phase specificity, primarily killing cells
undergoing DNA synthesis (S-phase) and also blocking the progression of cells
through the G1/S-phase boundary. Gemcitabine is metabolized intracellularly
3o by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate
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(dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is attributed to a
combination of two actions of the diphosphate and the triphosphate
nucleosides,
which leads to inhibition of DNA synthesis. First, gemcitabine diphosphate
inhibits ribonucleotide reductase, which is responsible for catalyzing the
s reactions that generate the deoxynucleoside triphosphates for DNA synthesis.
Inhibition of this enzyme by the diphosphate nucleoside causes a reduction in
the concentrations of deoxynucleotides, including dCTP. Second, gemcitabine
triphosphate competes with dCTP for incorporation into DNA. The reduction in
the intracellular concentration of dCTP (by the action of the diphosphate)
to enhances the incorporation of gemcitabine triphosphate into DNA (self-
potentiation). After the gemcitabine nucleotide is incorporated into DNA, only
one additional nucleotide is incorporated into DNA. After this addition, there
is
inhibition of further DNA synthesis.
Gemcitabine has shown promise in combination with CPT-11 as a
~s treatment for pancreatic cancer in Phase II studies.
MTA (multi-targeted antifolate) is an antimetabolite which is a folate
antagonist, dihydrofolate reductase inhibitor and thymidylate synthase
inhibitor.
It is provided for use as an intravenous solution and has been found to
inhibit
tumor growth in mice. It is currently being tested in humans for treatment of
Zo non-small lung cancer, mesothelioma, melanoma, bladder cancer, breast
cancer, pancreatic cancer, colorectal cancer, and other solid tumors.
Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity.
It is an orally administered prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR)
which
is converted to 5-fluorouracil in the body. In preclinical studies,
capecitabine
2s has demonstrated activity in colorectal, breast, and head and neck
carcinomas,
including those resistant to 5-FU.
The chemical name for capecitabine is 5'-deoxy-5-fluoro-N-
[(pentyloxy)carbonyl]-cytidine and has a molecular weight of 359.35.
Capecitabine has the following structural formula
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H
O ~ N\ /O
CH3 O / F IIO
..
HO ~OH
capecitabine
Capecitabine has a unique mechanism of activation that exploits the high
concentrations of the enzyme thymidine phosphorylase in tumor tissue
compared with healthy tissue, leading to tumor-selective generation of 5-FU.
s Two randomized, phase III studies have shown that oral capecitabine is
an effective first-line therapy for metastatic colorectal cancer, achieving a
superior response rate and at least equivalent survival and time to disease
progression compared with intravenous (i.v.) 5-FU/leucovorin (Mayo Clinic
regimen). Capecitabine also demonstrated a more favourable safety profile
to compared with the Mayo Clinic regimen.
The present invention is illustrated, but not limited, by the examples
below.
EXAMPLE 1
The administration of oral CPT-11 and oral capecitabine, alone and
is together, was evaluated against the human colon carcinoma strain HCT-116
implanted in Swiss-nude mice. When the two compounds were co-adminstered,
they were given one hour apart, with CPT-11 being given first. The volume of
administration of each compound was 0.2 ml p.o. The table below shows that
the maximum tolerated doses of both the single agents and the combined
2o compounds were highly active.
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Table 1
CPT-11/Capecitabine Simultaneous Oral Combination in HCT-116 Bearina Mice
Agent Daily DosageSchedule Logo cellT-C Comments
(mg/kg/adm) (Days Kill (days)
CPT-11 80 5-9, 12-16- - Toxic
CPT-11 48 " HNTD highly
active
CPT-11 29 " 2.1 30.1 Active
capecitabine1860 5-9, 12-16 Toxic
capecitabine1150 5-9, 12-16 HNTD highly
active
capecitabine713 5-9, 12-162.6 38.7 Active
capecitabine443 " 1.1 16.3 Active
CPT-11 + 28.8 5-9, 12-16- - Toxic
Capecitabine617
CPT-11 + 21.6 " 2.7 39.8 HNTD highly
Capecitabine463
active
CPT-11 + 14.4 " 2.2 32.4 Active
Capecitabine308
HNTD: Highest Non-Toxic Dose; T-C Tumor Growth Delay
These results indicated that other schedules could optimize the
s combination and indeed, Example 2 below shows that the semi-simultaneous
administration of capecitabine and CPT-11 results in a therapeutic combination
that is very active against the tumor tested; that is, the capecitabine/CPT-11
combination gave a logo cell kill value of greater than 2.8.
EXAMPLE 2
>o The co-administration of oral CPT-11 and oral capecitabine was
evaluated in Swiss-nude mice bearing early stage HCT-116 colon carcinoma.
Three dosage levels of CPT-11 were given alone on days 18-22 to establish the
highest non-toxic dose. Three dosage levels of capecitabine were given alone
on days 18-22 and 25-29. In the combination arm, two semi-simultaneous
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schedules were investigated. The first schedule involved administering
4 dosage levels of CPT-11 on days 18-22 with administration of 4 dosage levels
of capecitabine on days 18-22 and 25-29. In the second schedule, capecitabine
was administered first on days 18-22, followed by simultaneous administration
s with 4 dosage levels of CPT-11 on days 25-29.
The two combined sequences were found to be as active as the best
single agent and 42 % and 55 % of the highest non toxic dose of each single
agent could be administered without overlap in host toxicity. The order of
administration appeared to induce a difference in tolerance of the combined
to drugs. When capecitabine was administered first, the result seemed less
toxic
and was better tolerated than when CPT-11 was administered first. In both
modes of administration, however, the efficacy of the combination remained the
same.
The results obtained in the study of single agents CPT-11 and
is capecitabine and the combination of CPT-11/capecitabine are given below in
the following table. Three combinations were very active with a log cell kill
of
greater than 2.8.
Table 2
CPT-11/Capecitabine Semi-Simultaneous Oral Combination in
2o HCT-116 Bearing Mice
Agent Daily DosageSchedule Logo cellT-C Comments
(mg/kg/adm)(Days Kill (days)
CPT-11 155 18-22 - - Toxic
CPT-11 96 18-22 1.7 21.3 HNTD highly
active
CPT-11 60 18-22 1.7 21.4 Active
capecitabine1150 18-22 & 3.2 39.4 HNTD highly
25-29 active
capecitabine713 18-22 & 2.1 25.2 Active
25-29
capecitabine443 18-22 & 2.1 26.1 Active
25-29
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CPT-11 + 72 18-22 - - Toxic
capecitabine771 18-22 &
25-29
CPT-11 + 57.6 18-22 - - Toxic
capecitabine617 18-22 &
25-29
CPT-11 + 43.2 18-22 3.4 41.7 HNTD highly
capecitabine771 18-22 & active
25-29
CPT-11 + 28.8 18-22 2.3 27.7 Active
capecitabine308 18-22 &
25-29
capecitabine771 18-22 & - - Toxic
25-29
CPT-11 + 67.2 25-29
capecitabine617 18-22 & 3.1 38.6 HNTD highly
25-29
CPT-11 + 54.2 25-29 active
capecitabine463 18-22 & 3.3 40.0 Highly
25-29 active
CPT-11 + 38.1 25-29
capecitabine308 18-22 & 2.3 28.1 Active
25-29
CPT-11 + 25.2 25-29
HNTD: Highest Non-Toxic Dose; T-C: Tumor Growth Delay
EXAMPLE 3
The safety and efficacy of two schedules of irinotecan (CPT-11 )
s administered in combination with the standard dose of intermittent
capecitabine
were studied in patients with advanced/metastatic colorectal cancer.
The primary objective of the study was to compare the safety profiles of
the treatment schedules. The secondary objective was to compare tumour
response rates in the two treatment arms.
to Patients received irinotecan i.v. 300/mg/m in one of two dose schedules
in combination with intermittent, oral capecitabine in a 21-day treatment
cycle
(Figures 1 and 2).
Day 1 8 15 21
Irinotecan
300 mg/m as
a
90-minute i.v.
infusion
Oral capecitabine
1.250 mg/m Days 2-15
twice daily
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Figure 1. Treatment schedule for arm A.
Day 1 8 15 21
Irinotecan
150 mg/m as
a
90-minute i.v.
infusion
Oral capecitabine
1.250mg/m Days 2-15
twice daily
Figure 2. Treatment schedule for arm B.
A total of 19 patients with untreated or pretreated advanced colorectal
cancer were enrolled in this pilot study. Treatment was administered until
s disease progression occurred or for a maximum of 10 treatment cycles in
patients with tumour response or stable disease.
Patients with measurable, advanced or metastatic colorectal
adenocarcinoma were eligible for enrolment. These included patients aged 18-
75 years, with a life expectancy of at least 3 months and ECOG performance
io status 0-2. Patients aged 70-75 years were required to have ECOG
performance status 0-1.
The baseline characteristics of the 19 patients are shown in Table 3.
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Table 3
Patient characteristics
No. of patients
Treatment arm A 10
Treatment arm B* 9
Male/female 11 /8
Median age (years) [range] 56[33-70]
Primary tumour
Colon 13
Rectal 6
No prior chemotherapy 9
Prior chemotherapy+
Adjuvant setting 6
Metastatic setting 5
Metastatic sites
Liver 15
Lung 4
Locally relapsing tumor 2
Primary tumor 3
*One patient in treatment arm to treatment)
B died (not related after
receiving two treatment cycles
+One patient received treatment
in both settings
Safety was evaluated in all patients who received at least one dose of
study medication, with adverse events graded according to National Cancer
s Institute Common Toxicity Criteria (NCI CTC). Hand-foot syndrome was graded
1-3. Tumours were assessed by investigators at baseline and at 9-weekly
intervals based on World Health Organization criteria. The incidence of
treatment-related adverse events in the 19 patients treated to date is shown
in
Table 4. There were no grade 4 treatment-related adverse events. Only one
to patient required dose modification for the management of toxicities.
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Table 4
Incidence of treatment-related adverse events
No. of
patients
Treatment arm Treatment arm B
A
(n=10) (n=9)
Diarrhoea
Grade 2 4 4
Neutropenia
Grade 2 3 -
Grade 3 -
Hand-foot syndrome
Grade 2 4 3
Grade 3 1 -
Nausea
Grade 3 -
Eighteen patients were evaluable for response (Table 5).
Table 5
Antitumor activity of capecitabine/irinotecan combination reaiments in
patients
with advanced/metastatic colorectal cancer
No. of patients
Tumor response Treatment arm A Treatment arm
(n=10) B
(n=8)
Partial 8 5
Stable disease 2 1
Progressive disease 2
These preliminary data show that the two 21-day regimens combining
intermittent, oral capecitabine with i.v. irinotecan 300mg/m administered in a
single dose (dayl ) or divided into two equal doses (days 1 and 8) have
to favorable safety profiles and show encouraging antitumour activity in
patients
with advanced metastatic colorectal cancer. Of the 10 patients in arm A, 8 had
partial responses and 2 were stabilized. None showed progressive disease.
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Thus, the combination of CPT-11 and the pyrimidine derivative,
capecitabine, results in a very active combination for the treatment of
cancer,
such as colorectal cancer.
